Creatine ester pronutrient compounds and formulations

ABSTRACT

The present invention describes a method for providing creatine to an animal which includes receiving a creatine ester by the animal. The creatine ester is suitable for being modified by the animal to form creatine.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority under 35 U.S.C. §119(e)to U.S. Provisional Application No. 60/232,969 filed Sep. 14, 2000,which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention generally relates to the field of creatine,and particularly to creatine ester pronutrient compounds andformulations.

BACKGROUND OF THE INVENTION

[0003] Creatine is an endogenous nutrient produced naturally by theliver in most vertebrates. The uses of creatine are many, including useas a supplement to increase muscle mass and enhance muscle performanceas well as in emerging applications in the treatment of neuromusculardisorders.

[0004] Typically, creatine is taken up into muscle cells by specificreceptors and converted to phosphocreatine by creatine kinase. Musclecells, including skeletal muscle and the heart muscle, function byutilizing cellular energy released from the conversion of adenosinetriphosphate (ATP) to adenosine diphosphate (ADP). The amount ofphosphocreatine in the muscle cell determines the amount of time it willtake for the muscle to recover from activity and regenerate adenosinetriphosphate (ATP). Phosphocreatine is a rapidly accessible source ofphosphate required for regeneration of adenosine triphosphate (ATP) andsustained use of the muscle.

[0005] For example, energy used to expand and contract muscles issupplied from adenosine triphosphate (ATP). Adenosine triphosphate (ATP)is metabolized in the muscle by cleaving a phosphate radical to releaseenergy needed to contract the muscle. Adenosine diphosphate (ADP) isformed as a byproduct of this metabolism. The most common sources ofadenosine triphosphate (ATP) are from glycogen and creatine phosphate.Creatine phosphate is favored as a ready source of phosphate because itis able to resynthesize adenosine triphosphate (ATP) at a greater ratethan is typically achieved utilizing glycogen. Therefore, increasing theamount of creatine in the muscle increases the muscle stores ofphosphocreatine and has been proven to increase muscle performance andincrease muscle mass.

[0006] However, creatine itself is poorly soluble in an aqueoussolution. Further, creatine is not well absorbed from thegastrointestinal (GI) tract, which has been estimated to have a 1 to 14percent absorption rate. Thus, current products require large amounts ofcreatine to be administered to be effective, typically 5 grams or more.Additionally, side effects such as bloating, gastrointestinal (GI)distress, diarrhea, and the like are encountered with these highdosages.

[0007] Therefore, it would be desirable to provide an improved approachfor enhancing absorption of creatine.

SUMMARY OF THE INVENTION

[0008] Accordingly, the present invention is directed to creatine esterpronutrients and formulations. In a first aspect of the presentinvention, a method for providing creatine to an animal includesreceiving a creatine ester by the animal. The creatine ester is suitablefor being modified by the animal to form creatine.

[0009] In a second aspect of the present invention, a food supplementincludes a creatine ester suitable for being modified by an animal toform creatine. In a third aspect of the present invention, a method forproviding creatine to an animal includes receiving an ester derivativeof creatine by the animal. The ester derivative of creatine is suitablefor acting as a pronutrient in an animal.

[0010] In a fourth aspect of the present invention, a composition ofmatter includes:

[0011] wherein R represents an ester.

[0012] In a fifth aspect of the present invention, a method of producinga creatine pronutrient includes reacting a hydrated form of creatinewith an alcohol in an acidic environment wherein a product is formedincluding a creatine ester pronutrient.

[0013] It is to be understood that both the forgoing general descriptionand the following detailed description are exemplary and explanatoryonly and are not restrictive of the invention as claimed. Theaccompanying drawings, which are incorporated in and constitute a partof the specification, illustrate an embodiment of the invention andtogether with the general description, serve to explain the principlesof the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The numerous advantages of the present invention may be betterunderstood by those skilled in the art by reference to the accompanyingfigures in which:

[0015]FIG. 1A is an illustration depicting conversion of creatine tocreatinine;

[0016]FIG. 1B is a depiction of an exemplary embodiment of the presentinvention wherein the processing of creatine monohydrate versus acreatine ester by the body is shown;

[0017]FIG. 1C is a flow diagram illustrating an exemplary embodiment ofthe present invention wherein a pronutrient derivative of creatine iscreated through the modification of an acid moiety by ester bondattachment;

[0018]FIG. 1D is an illustration of an embodiment of the presentinvention in which a graph depicting solubility and partitioncoefficients of creatine ethyl ester versus creatine monohydrate areshown;

[0019]FIGS. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M and 2Nare illustrations of exemplary compounds of the present invention;

[0020]FIG. 3 is an illustration depicting an exemplary embodiment of thepresent invention wherein a creatine ethyl ester compound is produced bysolvating creatine monohydrate in dry ethyl alcohol in an acidicatmosphere;

[0021]FIG. 4 is an illustration of an embodiment of the presentinvention wherein additional methods and processes are shown for theproduction of a creatine ester; and

[0022]FIG. 5 is an illustration depicting an exemplary embodiment of thepresent invention wherein a creatine benzyl ester compound is producedby solvating anhydrous creatine in dry benzyl alcohol in an acidicatmosphere.

DETAILED DESCRIPTION OF THE INVENTION

[0023] Reference will now be made in detail to the presently preferredembodiments of the invention, examples of which are illustrated in theaccompanying drawings.

[0024] Referring generally now to FIGS. 1 through 5, exemplaryembodiments of the present invention are shown. Creatine,N-aminoiminomethyl-N-methylglycine, is an endogenous nutrient which maybe produced in the liver and kidneys. Typically, creatine is produced bythe transfer of the guanidine moiety of arginine to glycine, which isthen methylated to give creatine. Creatine may be represented by thefollowing formula:

[0025] Creatine phosphate is formed in the body and may be representedby the following formula:

[0026] Creatine is converted to creatine phosphate by the creatinekinase enzyme. The creatine phosphate transfers its phosphate toadenosine diphosphate (ADP) to accomplish the regeneration of adenosinetriphosphate (ATP). Adenosine triphosphate (ATP) may then be utilized bythe muscles as a source of energy. Thus, by providing a formulation andmethod for enhanced absorption of creatine, the muscle levels ofphosphocreatine will be elevated. As a result of this, muscle mass andperformance may be increased, thereby permitting a variety oftherapeutic applications.

[0027] Studies in the laboratory have shown that the aqueous solubilityand partition coefficient of creatine monohydrate are 15.6±2.1 mg/mL and0.015±0.007, respectively. The low oral bioavailability of creatine mayderive not only from its low lipophilicity and concomitant poor membranepermeability, but also from rapid conversion to creatinine in the acidiccondition of the stomach, and shown in FIG. 1A.

[0028] At a gastric pH range of 1-2, the equilibrium between creatineand creatinine shifts to the right such that the creatinine/creatineratio may be greater than or equal to 30. See Edgar, G.; Shiver, H. E.,The Equilibrium Between Creatine and Creatinine in Aqueous Solution. TheEffect of Hydrogen Ion. J. Amer. Chem. Soc. 1925, 47, 1179-1188, whichis herein incorporated by reference in its entirety.

[0029] Referring now to FIG. 1B, an embodiment of the present inventionis shown wherein creatine ester metabolism is shown. By providing acreatine ester, a more water-soluble compound will be provided than therelatively insoluble zwitterionic creatine, and increasedlipophilicities will allow for better membrane permeability.

[0030] For example, by masking the carboxylic acid functional group ofcreatinine by esterification, the formation of creatinine in the stomachwill be precluded, resulting in an efficient delivery of the creatineesters to the intestine where absorption may occur. Standard supplementscontaining creatine monohydrate undergo substantial conversion tocreatinine in the stomach. This, coupled with the low absorption ofcreatine in the intestine, leads to reduced amounts of creatine reachingthe muscle cell.

[0031] In contrast, creatine esters do not undergo conversion tocreatinine in the stomach and are more readily absorbed in theintestine. As a result, blood creatine concentrations are higher andthus more creatine is available to the muscle. As a result of this, theintestinal absorption of creatine ester will be significantly greaterthan that observed with creatine monohydrate. An additional advantage ofcreatine esters is that, as the creatine ester compound moves from theintestinal tissue into the bloodstream, the creatine ester compoundsthemselves are biologically inactive, but esterase enzymes present inboth the intestinal cells and the blood break the ester bonds ofcreatine ester, converting it to biologically active creatine. In otherwords, the advantages of the creatine ester are preserved duringtransport, such as increased solubility and permeability, but whenneeded, the creatine is available to be converted into its biologicallyactive form.

[0032] Compared to creatine monohydrate, the increased blood levels ofcreatine obtained with supplements containing the creatine estercompounds are expected to result in increased responses at the targettissue (i.e. muscle). Thus the increased stability and improvedabsorption of creatine ester results in much greater blood creatinelevels than can be achieved with creatine monohydrate supplements. Oncein the blood, creatine is transported into the muscle cells, where it isconverted to creatine phosphate that will then be consumed by the cellduring muscle performance.

[0033] Following is a brief overview of the various disease states thatmay be responsive to creatine supplementation. It should be noted thatthe proposed disease states below involve increasing creatine in adiverse array of cells including not only muscle but neurons andendothelial cells as well.

[0034] Parkinson's Disease

[0035] Parkinson's disease depletes dopamine levels in the brain. Energyimpairment may play a role in the loss of dopaminergic neurons. Studiesinvolving rats showed that a diet supplemented with creatine for 2 weeksresulted in only a 10% reduction in brain dopamine as compared to a 70%doparnine depletion in nonsupplemented rodents. See Matthews R T,Ferrante R J, Klivenyi P, Yang L, Klein A M, Mueller G, Kaddurah-Daouk Rand Beal M F. Creatine and cyclocreatine attenuate MPTP neurotoxicity.Exp Neurol 157: 142-149, (1999), which is herein incorporated byreference in its entirety. These pre-clinical studies suggest thatcreatine dietary supplements may have a positive therapeutic outcome inslowing the onset and decreasing the severity of the disease.

[0036] Huntington's Disease

[0037] Alterations in energy production may also contribute to thedevelopment of brain lesions in patients with Huntington's disease. Ratsfed a diet supplemented with creatine for 2 weeks responded better whenexposed to 3-nitropropionic acid which mimics the changes in energymetabolism seen with Huntington's disease. The creatine fed animals had83% less lesion volume than nonsupplemented animals (Matthews et al.,1999).

[0038] Mitochondrial Pathologies

[0039] Creatine supplementation increased the life-span of GP3Atransgenic mice (a model for amyotrophic lateral sclerosis) up to 26days. A study involving patients with a variety of neuromusculardisorders also benefited from creatine supplementation. See Klivenyi P,Ferrante R J, Matthews R T, Bogdanov M B, Klein A M, Andreassen O A,Mueller G, Wermer M, Kaddurah-Daouk R and Beal M F. Neuroprotectiveeffects of creatine in a transgenic animal model of anzyotrophic lateralsclerosis. Nat Med 5: 347-350, (1999), which is herein incorporated byreference in its entirety. Increases in high-density strengthmeasurements were seen in these patients following a short-term trail ofcreatine (10 g/d for 5 days with 5 g/d for 5 to 7 days). Creatinesupplementation also resulted in increased body weight in thesepatients.

[0040] Stroke

[0041] Creatine may also be useful in patients with hypoxia and ishemicbrain diseases such as stroke. Creatine has been shown to reduce damageto the brainstem and hippocampus resulting from hypoxia. See BalestrinoM, Rebaudo R and Lunardi G. Exogenous creatine delays anoxicdepolarization and protects from hypoxic damage: Dose-effectrelationship. Brain Res 816:124-130, (1999); and Dechent P, Pouwels P J,Wilken B, Hanefeld F and Frahm J. Increase of total creatine in humanbrain after oral supplementation of creatine-monohydrate. Am J Physiol277: R698-R704, (1999) which are herein incorporated by reference intheir entirety. This neuroprotection may be due to prevention of ATPdepletion. Studies suggest that supplementation of humans with creatinedoes increase brain levels of creatine. See Wick M, Fujimori H,Michaelis T and Frahm J. Brain water diffusion in normal andcreatine-supplemented rats during transient global ischemia. Magn ResonMed 42: 798-802, (1999); Michaelis T, Wick M, Fujimori H, Matsumura Aand Frahm J. Proton MRS of oral creatine supplementation in rats.Cerebral metabolite concentrations and ischemic challenge. NMR Biomed12: 309-314, (1999); and Malcon C, Kaddurah-Daouk R and Beal M.Neuroprotective effects of creatine administration against NMDA andmalonate toxicity. Brain Res 860: 195-198, (2000) which are hereinincorporated by reference in their entirety. High brain creatine levelsmay offer protection to ischemic brain injury.

[0042] Muscular Diseases

[0043] Patients with various muscular dystrophies supplemented withcreatine for 8 weeks showed a 3% increase in strength and a 10%improvement in neuromuscular symptom score. Short-term creatinesupplementation also improved strength in patients with rheumatoidarthritis, but did not change physical function. See Felber S, SkladalD, Wyss M, Kremser C, Koller A and Sperl W. Oral creatinesupplementation in Duchenne muscular dystrophy: A clinical and 31Pmagnetic resonance spectroscopy study. Neurol Res 22: 145-150 (2000),which is herein incorporated by reference in its entirety. Patients withMcArdles disease showed improvements when given creatine. Theimprovements included reduced frequency of muscle pain and increasedexercise performance and strength. Increases in exercise performancewhere also seen during ischemic episodes. See Willer B, Stucki G,Hoppeler H, Bruhlmann P and Krahenbuhl S. Effects of creatinesupplementation on muscle weakness in patients with rheumatoidarthritis. Rheumatology 39: 293-298, (2000), which is hereinincorporated by reference in its entirety.

[0044] Heart Disease

[0045] Given the role of creatine phosphate as an immediate and readilyaccessible source of phosphate for regeneration of ATP, it follows thatcreatine supplementation may have a favorable impact diseases of theheart. In patients with congestive heart failure creatinesupplementation produced an increase in exercise performance as measuredby strength and endurance. See Gordon A, Hultman E, Kaijser L,Kristjansson S, Rolf C J, Nyquist O and Sylven C. Creatinesupplementation in chronic heart failure increases skeletal musclecreatine phosphat and muscle performanmce. Cardiovasc Res 30: 413-418,(1995), which is herein incorporated by reference in its entirety. Anadditional consideration with ramifications in the management ofcardiovascular diseases is the report that creatine supplementation canlower cholesterol and triglyceride levels in humans. See Earnest C P,Almada A L and Mitchell T L. High-performance capillaryelectrophoresis-pure creatine monohydrate reduces blood lipids in menand women. Clin Sci (Colch) 91: 113-118, (1996), which is hereinincorporated by reference in its entirety.

[0046] Muscle Fatigue Secondary to Aging

[0047] Research on adults over 60-years of age suggest that creatinesupplementation may delay muscle fatigue, but does not affect bodycomposition or strength (Rawson and Clarkson, 2000). See Rawson E S andClarkson P M. Acute creatine supplementation in older men. Int J SportsMed 21: 71-75, (2000), which is herein incorporated by reference in itsentirety. As with many of the therapeutic implication studies, thesepreliminary experiments were performed over a short (i.e. less than30-day) period of time, where the effects of creatine supplementation onmuscle mass and strength may not be fully demonstrated. While theeffects observed in the elderly were not profound, these initial reportssuggest the health benefits to this growing population are promising.

[0048] Referring now to FIG. 1C, an exemplary embodiment of the presentinvention is shown wherein a pronutrient derivative of creatine iscreated through the modification of an acid moiety by ester bondattachment. Creatine 102 is changed by modifying an acid moiety throughester bond attachment 104. For example, creatine may be converted tocreatine ethyl ester 106, which has a formula as follows:

[0049] A creatine ester has the advantages of increased aqueoussolubility, increased absorption from the gastrointestinal (GI) tractresulting in increased bioavailability, and increased stability,especially for solution formulations. Increased bioavailability allowssmaller doses to be utilized with greater effect, thereby resulting infewer gastrointestinal side effects. Further, more varied formulationpossibilities are feasible, for example, the product may be formulatedin tablet or capsule form with dextrose and/or phosphate for ease of useand effectiveness.

[0050] Once the product is ingested 108, the body metabolizes andactivates the product by esterases 110, which may be found in theintestinal lumen, epithelial cells and the blood. The esterases convertthe product to creatine 114 and an alcohol 116. Thus, the currentinvention supplements the amount of creatine normally available to themuscle thereby increasing phosphocreatine levels and decreasing therecovery time required before the muscle can perform activity. Further,the resultant alcohols, such as ethanol, glycerol, benzyl alcohol,tert-butyl alcohol, are relatively harmless. See Budavari, S. (Ed.) TheMerck Index. Merck and Co., Inc., Whitehouse Station, N.J., 1996, whichis herein incorporated by reference in its entirety. For example, benzylalcohol is used as a pharmaceutical preservative.

[0051] Solubility and permeability are two important factors in theamount of a compound made available to an organism, otherwise known asbioavailability. Solubility refers to the amount of the compound thatmay be dissolved, wherein permeability refers to the ability of thecompound to penetrate across a barrier, such as a membrane, cell walland the like. In terms of solubility, creatine ethyl ester is a 2J, 2K,2L, 2M and 2N. For example, a mono-creatine glycerol, di-creatineglycerol, tricreatine glycerol and the like, may be utilized as apronutrient of the present invention, the formula for a tricreatineglycerol is as follows:

[0052] Another example of a creatine ester compound suitable for use asa pronutrient includes creatine phosphoester, the formula of which is asfollows:

[0053] Thus, the present invention provides multiple ester derivativesof creatine for use as pronutrients having increased solubility andpermeability over creatine itself. The advantages of creatinepronutrients of the present invention would be useful in athleticperformance markets, therapeutic markets targeting patients withdiseases involving reduced muscle performance/loss of muscle mass,livestock/animal food products market, and the like.

[0054] Referring generally now to FIGS. 3 and 4, an exemplary embodimentof the present invention is shown wherein the production of an esterderivative of creatine is shown. A creatine ester may be formed byreacting a hydrated form of creatine or anhydrous creatine with variousalcohols in an acidic atmosphere. Under these great deal more solublethat creatine. Utilizing a physiological buffer solution (PBS),laboratory analysis indicates that creatine monohydrate has a solubilitylimit of approximately 10 mg/ml. This value may be overly generous, as agreat deal of vortexing of the sample and brief heating of the sample to37 degrees Celsius had to be performed to even achieve that result.However, the creatine ethyl ester is readily soluble in room temperaturePBS with solubility over 200 mg/ml.

[0055] With regard to permeability, a laboratory analysis was performedcomparing the creatine monohydrate to creatine ethyl ester in MDCKmonolayers. The MDCK are a canine kidney epithelial cell line that hasbeen used as an in vitro model for assessing drug permeability. In theMDCK monolayers, creatine monohydrate showed approximately 10% flux overone hour. In other words, 10% of the original amount of creatinemonohydrate added to one side of the MDCK monolayer made it across tothe other side in a 60-minute period. For creatine ethyl ester, thepermeability is quite higher, averaging approximately 20% flux over onehour. Similar results are expected in a Caco-2 monolayer, which may beused as an in vitro model for intestinal absorption. Thus, the creatineester of the present invention has the unexpected result of bothincreased solubility and membrane permeability, and thus greaterbioavailability, as shown through the following table and graph depictedin FIG. 1D. Substance Conc. at Saturation mg/ml Partition CoefficientCreatine 15.6 +/− 2.1 0.015 +/− 0.007 Creatine Ethyl Ester 205.9 +/− 1.50.074 +/− 0.008 Creatine Benzyl Ester 89.26 +/− 0.8 0.106 +/− 0.01

[0056] Although a creatine ethyl ester compound has been described, itshould be apparent that a wide variety of creatine ester compounds andsalts thereof are contemplated by the present invention withoutdeparting from the spirit and scope thereof, examples of which are shownin FIGS. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, conditions, various esterprocreatine compounds may be formed, generally as white precipitates.The resultant creatine esters may be further purified by solvating in analcohol at elevated temperatures and then cooling to form the esterprocreatine compound. The final recrystallization step may not berequired, as the initial precipitate is generally pure. However, such anextra step may be useful to ensure that the purest form of the creatinepronutrient has been obtained.

[0057] For example, as shown in FIG. 3, creatine monohydrate may besolvated in dry ethyl alcohol in an atmosphere of hydrochloric acid atambient temperatures. The resultant creatine ethyl ester compound issolid at ambient temperatures. While not functionally necessary, theresultant creatine ethyl ester may be further purified with the use ofethyl alcohol at an elevated temperature to solvate the creatine ethylester away from possible contaminates contained in the solid reactionmaterial. Purified creatine ethyl ester may then be achieved uponcooling the solvated creatine ethyl ester. It should also be apparentthat anhydrous creatine may also be utilized without departing from thespirit and scope of the present invention.

[0058] Although the formulation of creatine ethyl ester is disclosed, itshould be apparent that a variety of creatine esters may be producedutilizing analogous reaction systems without departing from the spiritand scope of the present invention. See Dox., A. W.; Yoder, L.Esterification of Creatine. J. Biol. Chem. 1922, 67, 671-673, which isherein incorporated by reference in its entirety. For instance, avariety of methods of producing a creatine ester are contemplatedwithout departing from the spirit and scope of the present invention,such as the methods and process shown in FIG. 4, wherein X may include aleaving group. Although the use of creatine monohydrate is disclosed, avariety of creatine containing starting compounds are contemplated bythe present invention, creatine monohydrate being disclosed merelybecause of its availability.

[0059] Referring now to FIG. 5, an embodiment of the present inventionis shown wherein anhydrous creatine is solvated in dry benzyl alcohol inan atmosphere of hydrochloric acid at ambient temperatures to produce acreatine ester. The resultant creatine benzyl ester compound is a whitesolid at ambient temperatures. While not functionally necessary, theresultant creatine benzyl ester may be further purified with the use ofethyl alcohol at an elevated temperature to solvate the creatine benzylester away from possible contaminates. Purified creatine benzyl estermay then be achieved upon cooling the solvated creatine benzyl ester. Asstated earlier, the final recrystallization step may not be required asthe initial precipitate in relatively pure. However, such an extrapurification step may be useful to ensure that the most pure form of thecompound has been obtained.

[0060] As discussed earlier, creatine esters may also be synthesizedfrom anhydrous creatine using esterification methods and isolated astheir hydrochloride salts. For example, creatine ethyl esterhydrochloride may be synthesized by treatment of anhydrous creatine withethanolic HCl at room temperature. See Dox., A. W.; Yoder, L.Esterification of Creatine. J. Biol. Chem., 67, 671-673, (1922) which isherein incorporated by reference in its entirety.

[0061] Using this method, creatine ethyl ester hydrochloride wassynthesized in 74% yield after a single recrystallization from ethanol.

[0062] Creatine esters creatine benzyl ester hydrochloride and creatinemonoglycerate ester hydrochloride may similarly be obtained by exposureof anhydrous creatine with excess HCl-saturated benzyl alcohol andglycerol, respectively. It should be apparent that stereoisomers, suchas a stereoisomers of creatine monoglycerate ester hydrochloride, andthe compounds shown in FIGS. 2B, 2E, 2F, 2G, 2J and the like, are alsocontemplated by the present invention.

[0063] Creatine tert-butyl ester hydrochloride may be obtained bytreatment of creatine acid chloride with tert-butanol and zinc chloride.See Rak, J.; Lubkowski, J.; Nikel, I.; Przubulski, J.; Blazejowski, J.Thermal Properties, Crystal Lattice Energy, Mechanism and Energetics ofthe Thermal Decomposition of Hydrochlorides of 2-Amino Acid Esters,Thermochimica Acta 171, 253-277 (1990); Yadav, J. S.; Reddy, G. S.;Srinivas, D.; Himabindu, K. Zinc Promoted Mild and Efficient Method forthe Esterification of Acid Chlorides with Alcohols, Synthetic Comm. 28,2337-2342 (1998). Creatine tert-butyl ester hydrochloride may also beobtained by treatment of anhydrous creatine with tert-butanol andanhydrous magnesium sulfate and catalytic sulfuric acid. See Wright, S.W.; Hageman, D. L.; Wright, A. S.; McClure, L. D. ConvenientPreparations of t-Butyl Esters and Ethers from t-Butanol, TetrahedronLett. 38, 7345-7348 (1997), which are herein incorporated by referencein their entireties.

[0064] Bis creatine glycerate ester dihydrochloride ester, may beobtained by treatment of creatine acid chloride with a half-molarequivalent of anhydrous glycerol. See Rak, J.; Lubkowski, J.; Nikel, L.;Przubulski, J.; Blazejowski, J. Thermal Properties, Crystal LatticeEnergy, Mechanism and Energetics of the Thermal Decomposition ofHydrochlorides of 2-Amino Acid Ester, Thermochimica Acta 71, 253-277(1990), which is herein incorporated by reference in its entirety.

[0065] Alternatives to these methods include transesterificationreaction of CE1 using either catalytic diphenyl ammonium triflate andtrimethylsilyl chloride (Wakasugi et al., 2000) or catalytic potassiumtert-butoxide and 1 equivalent of tert-butyl acetate. Creatine acidchloride may also be used rather than anhydrous creatine in theesterification reactions. See Wakasugi, K.; Misake, T.; Yamada, K.;Tanabe, Y. Diphenylammonium triflate (DPAT): Efficient Catalyst forEsterification of Carboxylic Acids and For Transesterification ofCarboxylic Esters With Nearly Equimolar Amounts of Alcohols, TetrahedronLett. 41, 5249-5252 (2000), which is herein incorporated by reference inits entirety.

[0066] Regioselectivity problems in the formation of creatine esters,such as creatine monoglycerate ester hydrochloride, Bis creatineglycerate ester dihydrochloride ester, and the like, may be addressed byselective esterification of the primary alcohol functional group(s) ofglycerol with creatine acid chloride in the presence ofN,N-diisopropylethylamine or 2,4,6-collidine at low temperatures. SeeIshihara, K.; Kurihara, H.; Yamamoto, H. An Extremely Simple,Convenient, and Selective Method for Acetylating Primary Alcohols in thePresence of Secondary Alcohols, J. Org Chem. 58, 3791-3793 (1993), whichis herein incorporated by reference in its entirety.

[0067] Creatine esters may be purified by crystallization, flash columnchromatography, and the like, if desired, and the structures and purityconfirmed by analytical HPLC, ¹H and ¹³C NMR, IR, melting point andelemental analysis. The following data was obtained through nuclearmagnetic resonance spectroscopy of the corresponding compounds:

[0068] Creatine Ethyl Ester Hydrochloride

[0069]¹H NMR (500 MHz, CDCl₃) δ 1.12 (dq, J=6.0 Hz, J=1.0 Hz, 3H), 2.91,(s, 3H), 4.10-4.11 (m, 4H).

[0070] Creatine Benzyl Ester Hydrochloride

[0071]¹H NMR (500 MHz, DMSO-d₆) δ 3.03 (s, 3H), 4.13 (s, 2H), 5.06 (s,2H), 7.22-7.38 (m, 5H).

[0072] It is understood that the specific order or hierarchy of steps inthe methods disclosed are examples of exemplary approaches. Based upondesign preferences, it is understood that the specific order orhierarchy of steps in the method can be rearranged while remainingwithin the scope of the present invention. The accompanying methodclaims present elements of the various steps in a sample order, and arenot meant to be limited to the specific order or hierarchy presented.

[0073] It is believed that the creatine ester pronutrient compounds andformulations of the present invention and many of its attendantadvantages will be understood by the forgoing description. It is alsobelieved that it will be apparent that various changes may be made inthe form, construction and arrangement of the components thereof withoutdeparting from the scope and spirit of the invention or withoutsacrificing all of its material advantages. The form herein beforedescribed being merely an explanatory embodiment thereof. It is theintention of the following claims to encompass and include such changes.

What is claimed is:
 1. A method for providing creatine to an animal,comprising: receiving a creatine ester by the animal, wherein thecreatine ester is suitable for being modified by the animal to formcreatine.
 2. The method as described in claim 1, wherein the creatineester is suitable for being formed in a solid form capable of beingingested by the animal.
 3. The method as described in claim 2, whereinthe solid form includes the creatine ester and at least one of dextroseand phosphate.
 4. The method as described in claim 2, wherein the solidform is configured as at least one of a tablet and a capsule.
 5. Themethod as described in claim 1, wherein the creatine ester is suitablefor liquid delivery.
 6. The method as described in claim 5, wherein thecreatine ester includes at least one of an aqueous solution andemulsion.
 7. The method as described in claim 1, wherein the creatineester includes at least one of creatine ethyl ester, creatine benzylester, creatine phosphoester, monocreatine glycerol, t-butyl creatineester, dicreatine glycerol and tricreatine glycerol.
 8. The method asdescribed in claim 1, wherein the creatine ester is received by theanimal, the creatine ester is modified by the animal into creatine andan alcohol.
 9. The method as described in claim 8, wherein the creatineester is modified by the animal into creatine and alcohol by anesterase.
 10. The method as described in claim 8, wherein the creatineester is modified by at least one of an intestinal lumen, epithelialcell and blood of the animal into creatine.
 11. The method as describedin claim 1, further comprising forming a creatine ester, wherein an acidmoiety of creatine is modified to provide an ester bond.
 12. The methodas described in claim 1, wherein the animal includes a human andlivestock.
 13. A food supplement, comprising: a creatine ester suitablefor being modified by an animal to form creatine.
 14. The foodsupplement as described in claim 13, wherein the creatine ester issuitable for being formed in a solid form capable of being ingested bythe animal.
 15. The food supplement as described in claim 14, whereinthe solid form includes the creatine ester and at least one of dextroseand phosphate.
 16. The food supplement as described in claim 14, whereinthe solid form is configured as at least one of a tablet and a capsule.17. The food supplement as described in claim 13, wherein the creatineester is suitable for liquid delivery.
 18. The food supplement asdescribed in claim 17, wherein the creatine ester includes at least oneof an aqueous solution and emulsion.
 19. The food supplement asdescribed in claim 13, wherein the creatine ester includes at least oneof creatine ethyl ester, creatine benzyl ester, creatine phosphoester,monocreatine glycerol, t-butyl creatine ester, dicreatine glycerol andtricreatine glycerol.
 20. The food supplement as described in claim 13,wherein the creatine ester is received by the animal, the creatine esteris modified by the animal into creatine and an alcohol.
 21. The foodsupplement as described in claim 20, wherein the creatine ester ismodified by the animal into creatine and alcohol by an esterase.
 22. Thefood supplement as described in claim 20, wherein the creatine ester ismodified by at least one of an intestinal lumen, epithelial cell andblood of the animal into creatine.
 23. The food supplement as describedin claim 13, further comprising forming a creatine ester, wherein anacid moiety of creatine is modified to provide an ester bond.
 24. Thefood supplement as described in claim 13, wherein the animal includes atleast one of human and livestock.
 25. A method for providing creatine toan animal, comprising: receiving an ester derivative of creatine by theanimal, wherein the ester derivative of creatine is suitable for actingas a pronutrient in an animal.
 26. The method as described in claim 25,wherein the ester derivative of creatine acts as a pronutrient in thegastrointestinal tract of the animal.
 27. The method as described inclaim 25, wherein the pronutrient is metabolized by the animal to formcreatine.
 28. The method as described in claim 27, wherein thepronutrient is metabolized by an esterase.
 29. The method as describedin claim 28, wherein the pronutrient is metabolized by esterases in atleast one of an intestinal lumen, epithelial cell and blood.
 30. Themethod as described in claim 25, wherein the pronutrient is metabolizedby the animal for form an alcohol.
 31. The method as described in claim25, wherein the creatine ester is suitable for being formed in a solidform capable of being ingested by the animal.
 32. The method asdescribed in claim 31, wherein the solid form includes the creatineester and at least one of dextrose and phosphate.
 33. The method asdescribed in claim 31, wherein the solid form is configured as at leastone of a tablet and a capsule.
 34. The method as described in claim 25,wherein the creatine ester is suitable for liquid delivery.
 35. Themethod as described in claim 34, wherein the creatine ester includes atleast one of an aqueous solution and emulsion.
 36. The method asdescribed in claim 25, wherein the creatine ester includes at least oneof creatine ethyl ester, creatine benzyl ester, creatine phosphoester,monocreatine glycerol, t-butyl creatine ester, dicreatine glycerol andtricreatine glycerol.
 37. The method as described in claim 25, whereinthe creatine ester is received by the animal, the creatine ester ismodified by the animal into creatine and an alcohol.
 38. The method asdescribed in claim 37, wherein the creatine ester is modified by theanimal into creatine and alcohol by an esterase.
 39. The method asdescribed in claim 37, wherein the creatine ester is modified by atleast one of an intestinal lumen, epithelial cell and blood of theanimal into creatine.
 40. The method as described in claim 25, furthercomprising forming a creatine ester, wherein an acid moiety of creatineis modified to provide an ester bond.
 41. The method as described inclaim 25, wherein the animal includes human and livestock.
 42. Acomposition of matter, comprising:

wherein R represents an ester.
 43. The composition of matter asdescribed in claim 42, wherein R represents an ester so as to form acomposition of matter including at least one of creatine benzyl ester,creatine phosphoester, monocreatine glycerol, t-butyl creatine ester,dicreatine glycerol and tricreatine glycerol.
 44. The composition ofmatter as described in claim 42, wherein the composition of matter issuitable for being converted to creatine upon receipt by an animal. 45.The composition of matter as described in claim 44, wherein upon receiptof the composition of matter by the animal, creatine and an alcohol areformed.
 46. The composition of matter as described in claim 42, whereina salt is formed of the composition of matter.
 47. A method of producinga creatine pronutrient, comprising: reacting at least one of ananhydrous creatine and hydrated form of creatine with an alcohol in anacidic environment, wherein a product is formed including a creatineester pronutrient.
 48. The method as described in claim 47, wherein thehydrated form of creatine includes creatine monohydrate.
 49. The methodas described in claim 47, wherein the alcohol includes at least one ofethyl alcohol and benzyl alcohol.
 50. The method as described in claim47, wherein the acidic environment is achieved through hydrochloric acidbeing present.
 51. The method as described in claim 47, furthercomprising purifying the product.
 52. The method as described in claim51, wherein the product is purified by solvating the product in analcohol and then cooling to form purified creatine ester.